Surgical implantation of biological tissues and prostheses made using biological tissues (collectively, “bioprosthetic devices”) is well known and accepted in various medical fields. Examples of well known bioprosthetic devices include heart valves, vascular grafts, skin grafts, Dora mater grafts, pericardium grafts, cartilage grafts and implants, urinary bladder prostheses, ligament prostheses, tendon prostheses, and the like. Other known bioprosthetic devices comprise polymer-encapsulated cells and cell-seeded tissue engineered scaffolds. A significant advantage of valvular bioprosthetic devices, relative to prostheses which do not comprise biological tissue, is that blood coagulation induced by the presence of a prosthesis is usually much lower when a bioprosthetic device is used than when a non-biological prosthesis is used. Also, bioprosthetic devices generally exhibit a reduced incidence of catastrophic failure, relative to non-biological prostheses.
Bioprosthetic devices may be constructed entirely of biological tissue, or they may comprise a combination of biological tissue and synthetic materials. Furthermore, the biological tissue of the prosthesis may be derived from the recipient (usually a human patient), from an animal of the same species as the recipient, from an animal of a species different from the recipient, or from artificially cultured tissues or cells of various origins. Regardless of the source of the biological tissue, a major shortcoming of bioprostheses is that the devices deteriorate over time.
Deterioration of bioprosthetic devices has several manifestations. Implantation of a non-treated biological tissue particularly one derived from an animal of a species different from the recipient) frequently induces an immune response to the tissue in the recipient. Such an immune response causes elements of the recipient's immune system to bind with and destroy the implanted tissue, leading to rapid failure of the device. Even in the absence of an immune response, mechanical stresses exerted upon an implanted tissue (particularly vascular tissues and other implanted tissues which are frequently mechanically stressed) can induce mechanical degradation of the tissue, resulting in thinning or tearing of the tissue or loss of important biological characteristics (e.g. resilience or flexibility). Others have demonstrated that the mechanical and antigenic properties of bioprosthetic devices can be improved by treating the devices prior to implantation with various agents. These pre-implantation treatment methods are generally referred to in the art as “fixation” or “cross-linking.”
The most common agent used for fixation of valvular and other collagenous bioprosthetic devices is glutaraldehyde. Other fixative agents which have been used include aldehydes other than glutaraldehyde, various diisocyanates, various polyepoxide ethers, and various carbodiimides as described, for example in U.S. Pat. No. 5,447,536, U.S. Pat. No. 5,782,931, and other U.S. patents which are, as of the filing date of this application, classified in U.S. class/subclass 8/94.11. These prior art fixation methods generally involve treating a bioprosthetic device, prior to implantation, with a chemical agent which, either alone or in combination with another chemical agent, creates a covalent linkage between and within reactive groups of extracellular protein molecules (e.g. amino or carboxyl groups of collagen, elastin, or both). In many fixation methods, this cross-linking step is followed by an additional treatment to retard post-implantation calcification in or on the device.
A shortcoming of prior art bioprosthesis fixation methods is that cross-linking of extracellular proteins in the bioprosthesis inhibits degradation of the bioprosthesis only to a limited degree. Thus, the useful life of the bioprosthesis may be shorter than the remaining life span of the recipient thereof, meaning that the device has to be replaced. It would be tremendously advantageous to extend the useful life of bioprosthetic devices. The present invention provides various methods of extending the useful life of bioprosthetic devices longer than is possible using prior art fixation methods.